TY - JOUR
T1 - Repeat expansions nested within tandem CNVs
T2 - a unique structural change in GLS exemplifies the diagnostic challenges of non-coding pathogenic variation
AU - Fazal, Sarah
AU - Danzi, Matt C.
AU - van Kuilenburg, Andr? B. P.
AU - Reich, Selina
AU - Trasch?tz, Andreas
AU - Bender, Benjamin
AU - Leen, Ren?
AU - Toro, Camilo
AU - Usdin, Karen
AU - Hayward, Bruce
AU - Adams, David R.
AU - van Karnebeek, Clara D. M.
AU - Ferreira, Carlos R.
AU - D'Sousa, Precilla
AU - Network, Undiagnosed Diseases
AU - Tekin, Mustafa
AU - Z?chner, Stephan
AU - Synofzik, Matthis
N1 - Funding Information: This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, No. 441409627), as part of the PROSPAX consortium under the frame of EJP RD, and the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP No. 825575 (to M.S. and S.Z. as associated partner). We further received NIH support in grant 5U01HG010230 via the UDN site Miami (to M.T. and S.Z.) and grant 5R01NS072248 to S.Z. This work was also supported by the American Heart Association predoctoral fellowship awarded to S.F. (#917392). Additionally, we received a grant from the Intramural Program of the NIDDK (1ZIADK057808-14) to K.U., the ‘Stichting Steun Emma Kinderziekenhuis’ and ‘Stofwisselkracht’ to A.B.P.v.K., ‘Stichting Metakids’ to C.v.K., and the Clinician Scientist Programme of the University of Tübingen (grant number #439-0-0 to A.T.). The NIH Undiagnosed Diseases Network and the NIH Undiagnosed Diseases Program are supported by the Common Fund from the Office of the NIH Director. Publisher Copyright: © 2022 The Author(s).
PY - 2023/1/1
Y1 - 2023/1/1
N2 - Glutaminase deficiency has recently been associated with ataxia and developmental delay due to repeat expansions in the 5'UTR of the glutaminase (GLS) gene. Patients with the described GLS repeat expansion may indeed remain undiagnosed due to the rarity of this variant, the challenge of its detection and the recency of its discovery. In this study, we combined advanced bioinformatics screening of ~3000 genomes and ~1500 exomes with optical genome mapping and long-read sequencing for confirmation studies. We identified two GLS families, previously intensely and unsuccessfully analyzed. One family carries an unusual and complex structural change involving a homozygous repeat expansion nested within a quadruplication event in the 5'UTR of GLS. Glutaminase deficiency and its metabolic consequences were validated by in-depth biochemical analysis. The identified GLS patients showed progressive early-onset ataxia, cognitive deficits, pyramidal tract damage and optic atrophy, thus demonstrating susceptibility of several specific neuron populations to glutaminase deficiency. This large-scale screening study demonstrates the ability of bioinformatics analysis-validated by latest state-of-the-art technologies (optical genome mapping and long-read sequencing)-to effectively flag complex repeat expansions using short-read datasets and thus facilitate diagnosis of ultra-rare disorders.
AB - Glutaminase deficiency has recently been associated with ataxia and developmental delay due to repeat expansions in the 5'UTR of the glutaminase (GLS) gene. Patients with the described GLS repeat expansion may indeed remain undiagnosed due to the rarity of this variant, the challenge of its detection and the recency of its discovery. In this study, we combined advanced bioinformatics screening of ~3000 genomes and ~1500 exomes with optical genome mapping and long-read sequencing for confirmation studies. We identified two GLS families, previously intensely and unsuccessfully analyzed. One family carries an unusual and complex structural change involving a homozygous repeat expansion nested within a quadruplication event in the 5'UTR of GLS. Glutaminase deficiency and its metabolic consequences were validated by in-depth biochemical analysis. The identified GLS patients showed progressive early-onset ataxia, cognitive deficits, pyramidal tract damage and optic atrophy, thus demonstrating susceptibility of several specific neuron populations to glutaminase deficiency. This large-scale screening study demonstrates the ability of bioinformatics analysis-validated by latest state-of-the-art technologies (optical genome mapping and long-read sequencing)-to effectively flag complex repeat expansions using short-read datasets and thus facilitate diagnosis of ultra-rare disorders.
KW - 5' Untranslated Regions
KW - Ataxia/diagnosis
KW - Glutaminase/genetics
KW - Humans
KW - Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=85146364889&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/ddac173
DO - https://doi.org/10.1093/hmg/ddac173
M3 - Article
C2 - 35913761
SN - 0964-6906
VL - 32
SP - 46
EP - 54
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 1
ER -